Appendix D - Dossier (PDF) - Tera

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date: 20–JUL–2005 5. Toxicity Substance ID: 71–43–2 ______________________________________________________________________________ raised, however, about the exposure methods that were applied to this population of Chinese workers. They conclude that these issues do not undermine the finding of significantly elevated risks of lymphoreticular disorders in Chinese workers at average exposures substantially below those assigned to the Pliofilm cohort. Source: A.K. Mallett Surrey 17–MAR–2002 (487) Species: human Sex: Remark: This paper continues debate of the strengths and weaknesses of the health survey conducted by the Chinese Academy of Preventative Medicine on 528,729 benzene–exposed workers (the NCI–CAPM study). It follows a published response by Hayes et al (2001, Am J Ind Med, 40, 117) to earlier comments from this author (Wong). A key discussion point is the reliability of exposure estimates used to support the NCI–CAPM study. Wong notes that these were consistently and substantially lower than actual exposures, documented in Chinese occupational medicine journals, which show that these individuals were exposed to levels of benzene that exceeded the 40 mg/m3 national standard in place in China at that time. Exposures in the range 50–500 mg/m3 were said to be commonplace. Wong contrasts this information with a claim that the NCI–CAPM study was sufficiently reliable to extend risk estimates to levels of exposure below 10 ppm. Source: A.K. Mallett Surrey 04–MAR–2003 (1275) Species: human Sex: Remark: This review provides a comprehensive analysis of metabolic and mechanistic factors believed to be involved in benzene–induced leukemia. It includes the following elements: Appendix D: Benzene SIDS Dossier * Historical perspective * Benzene toxicity * Benzene and leukemia * Animal carcinogenicity studies * Interaction of benzene metabolites * Species differences in metabolism * Covalent binding to macromolecules * Myelodysplastic syndrome * Chromosomal damage * Studies using myeloblasts in culture * Mechanisms of toxicity/leukemogenesis * Issues in benzene risk assessment The author discusses uncertainties in our current – 552/957 –
date: 20–JUL–2005 5. Toxicity Substance ID: 71–43–2 ______________________________________________________________________________ understanding of the complex mechanisms by which benzene induces leukemia. If this is a result of covalent binding of benzene metabolites to DNA it would be a non–threshold event, while other mechanisms, perhaps involving an alteration in protein functionality, would require some finite level of exposure and the dose–response curve would exhibit a threshold. Experimental results are available that support both mechanisms, however the author notes that evidence is emerging which indicates that specific chromosomal aberrations resulting from benzene–related changes in specific structural proteins or enzymes are more important than DNA adduct formation. The enzymes involved in benzene metabolism and detoxication, the control and function of interleukins in bone marrow by benzene metabolites, the control of apoptosis in bone marrow cells and the inhibition of topoisomerase II are all protein–mediated and part of the process of leukemogenesis. The most significant genotoxic event appears to be a series of chromosomal translocations, the mechanisms of which are not known. This movement, intact, of a segment of one chromosome to a sister chromosome is a highly ordered process that is unlikely an uncontrolled event and is probably protein mediated. Such considerations suggest that DNA damage preceding benzene–induced leukemogenesis is a protein–mediated threshold event. Source: A.K. Mallett Surrey 26–JAN–2003 (1072) Species: human Sex: Remark: Chinese language paper, translation unavailable: ABSTRACT: "The relationship between glutathione–S–transferase M1(GST.mu.) gene deletion and leukemia in workers exposed to benzene was studied. A matched population–based case–control survey with multivariate Logistic regression analysis was conducted in this study. In the population of 34 patients and their matched controls, the absence of the GST.mu. genotype conferred odds ratio of 3.6. It suggested that GST.mu. was an important determinant of heterogeneity in individual susceptibility to leukemia associated with exposure to benzene. The single–variance analysis indicated that these markedly significant factors were GSF.mu. gene deletion, GSF.mu. isoenzyme in workshop air. The multivariate anal. indicated that these markedly significant factors were GSF.mu. gene deletion, duration of exposure to benzene and GSF.mu. isoenzyme activity." Source: A.K. Mallett Surrey Conclusion: GSF.mu gene deletion may be associated with increased risk of leukemia in workers exposed to benzene. 04–MAR–2003 (1232) Appendix D: Benzene SIDS Dossier – 553/957 –
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Appendix D: Benzene SIDS Dossier
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date: 20-JUL-2005 1. General Inform
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date: 20-JUL-2005 2. Physico-chemic
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date: 20-JUL-2005 3. Environmental
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date: 20-JUL-2005 4. Ecotoxicity Su
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date: 20-JUL-2005 5. Toxicity Subst
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date: 20-JUL-2005 7. Eff. Against T
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date: 20-JUL-2005 9. References Sub
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